tbuckley/cabot-search huggingface dataset:
Drug repurposing for the treatment of COVID-19: Targeting nafamostat to the lungs by a liposomal delivery system
Authors: Philipp Reus, Hadar Guthmann, Nadja Uhlig, Majd Agbaria, Leila Issmail, Valentina Eberlein, Mirjam M. Nordling-David, Doaa Jbara-Agbaria, Sandra Ciesek, Denisa Bojkova, Jindrich Cinatl, Anke Burger-Kentischer, Steffen Rupp, Andrea Zaliani, Thomas Grunwald, Philip Gribbon, Aimo Kannt, Gershon Golomb
Journal: Journal of Controlled Release (2023)

Despite tremendous global efforts since the beginning of the COVID-19 pandemic, still only a limited number of prophylactic and therapeutic options are available. Although vaccination is the most effective measure in preventing morbidity and mortality, there is a need for safe and effective post-infection treatment medication. In this study, we explored a pipeline of 21 potential candidates, examined in the Calu-3 cell line for their antiviral efficacy, for drug repurposing. Ralimetinib and nafamostat, clinically used drugs, have emerged as attractive candidates. Due to the inherent limitations of the selected drugs, we formulated targeted liposomes suitable for both systemic and intranasal administration. Non-targeted and targeted nafamostat liposomes (LipNaf) decorated with an Apolipoprotein B peptide (ApoB-P) as a specific lung-targeting ligand were successfully developed. The developed liposomal formulations of nafamostat were found to possess favorable physicochemical properties including nano size (119-147 nm), long-term stability of the normally rapidly degrading compound in aqueous solution, negligible leakage from the liposomes upon storage, and a neutral surface charge with low polydispersity index (PDI). Both nafamostat and ralimetinib liposomes showed good cellular uptake and lack of cytotoxicity, and non-targeted LipNaf demonstrated enhanced accumulation in the lungs following intranasal (IN) administration in non-infected mice. LipNaf retained its anti-SARS-CoV 2 activity in Calu 3 cells with only a modest decrease, exhibiting complete inhibition at concentrations >100 nM. IN, but not intraperitoneal (IP) treatment with targeted LipNaf resulted in a trend to reduced viral load in the lungs of K18-hACE2 mice compared to targeted empty Lip. Nevertheless, upon removal of outlier data, a statistically significant 1.9-fold reduction in viral load was achieved. This observation further highlights the importance of a targeted delivery into the respiratory tract. In summary, we were able to demonstrate a proof-of-concept of drug repurposing by liposomal formulations with anti-SARS-CoV-2 activity. The biodistribution and bioactivity studies with LipNaf suggest an IN or inhalation route of administration for optimal therapeutic efficacy.
Overcoming the challenges of using automated technologies for public health evidence synthesis
Authors: Lucy Hocking, Sarah Parkinson, Avery Adams, Emmanuel Molding Nielsen, Cecilia Ang, Helena de Carvalho Gomes
Journal: Eurosurveillance (2023)

Many organisations struggle to keep pace with public health evidence due to the volume of published literature and length of time it takes to conduct literature reviews. New technologies that help automate parts of the evidence synthesis process can help conduct reviews more quickly and efficiently to better provide up-to-date evidence for public health decision making. To date, automated approaches have seldom been used in public health due to significant barriers to their adoption. In this Perspective, we reflect on the findings of a study exploring experiences of adopting automated technologies to conduct evidence reviews within the public health sector. The study, funded by the European Centre for Disease Prevention and Control, consisted of a literature review and qualitative data collection from public health organisations and researchers in the field. We specifically focus on outlining the challenges associated with the adoption of automated approaches and potential solutions and actions that can be taken to mitigate these. We explore these in relation to actions that can be taken by tool developers (e.g. improving tool performance and transparency), public health organisations (e.g. developing staff skills, encouraging collaboration) and funding bodies/the wider research system (e.g. researchers, funding bodies, academic publishers and scholarly journals).
Investigation of an international water polo tournament in Czechia as a potential source for early introduction of the SARS-CoV-2 Omicron variant into Belgium, Switzerland and Germany, November 2021
Authors: Christoph Rudin, Nena Bollen, Samuel L Hong, Fanny Wegner, Lida Politi, Kassiani Mellou, Caspar Geenen, Sarah Gorissen, Bruno Verhasselt, Keith Durkin, Coralie Henin, Anne-Sophie Logist, Simon Dellicour, Tobias Resa, Tanja Stadler, Piet Maes, Lize Cuypers, Emmanuel André, Adrian Egli, Guy Baele
Journal: Eurosurveillance (2023)

BackgroundThe earliest recognised infections by the SARS-CoV-2 Omicron variant (Pango lineage B.1.1.529) in Belgium and Switzerland suggested a connection to an international water polo tournament, held 12-14 November 2021 in Brno, Czechia.AimTo study the arrival and subsequent spread of the Omicron variant in Belgium and Switzerland, and understand the overall importance of this international sporting event on the number of infections in the two countries.MethodsWe performed intensive forward and backward contact tracing in both countries, supplemented by phylogenetic investigations using virus sequences of the suspected infection chain archived in public databases.ResultsThrough contact tracing, we identified two and one infected athletes of the Belgian and Swiss water polo teams, respectively, and subsequently also three athletes from Germany. In Belgium and Switzerland, four and three secondary infections, and three and one confirmed tertiary infections were identified. Phylogenetic investigation demonstrated that this sporting event played a role as the source of infection, but without a direct link with infections from South Africa and not as a superspreading event; the virus was found to already be circulating at that time in the countries involved.ConclusionThe SARS-CoV-2 Omicron variant started to circulate in Europe several weeks before its identification in South Africa on 24 November 2021. Accordingly, it can be assumed that travel restrictions are usually implemented too late to prevent the spread of newly detected SARS-CoV-2 variants to other regions. Phylogenetic analysis may modify the perception of an apparently clear result of intensive contact tracing.
Hyaluronic Acid‐Based Reactive Oxygen Species‐Responsive Multifunctional Injectable Hydrogel Platform Accelerating Diabetic Wound Healing
Authors: Chen Shi, Ying Zhang, Guanfu Wu, Zhangyu Zhu, Haiping Zheng, Ximeng Sun, Yongyuan Heng, Shaowei Pan, Haonan Xiu, Jing Zhang, Zhaowei Yin, Ziyi Yu, Bin Liang
Journal: Advanced Healthcare Materials (2023)

Diabetic wounds are more likely to develop into complex and severe chronic wounds. The objective of this study is to develop and assess a reactive oxygen species (ROS)-responsive multifunctional injectable hydrogel for the purpose of diabetic wound healing. A multifunctional hydrogel (HA@Cur@Ag) is successfully synthesized with dual antioxidant, antibacterial, and anti-inflammatory properties by crosslinking thiol hyaluronic acid (SH-HA) and disulfide-bonded hyperbranched polyethylene glycol (HB-PBHE) through Michael addition; while, incorporating curcumin liposomes and silver nanoparticles (AgNPs). The HA@Cur@Ag hydrogel exhibits favorable biocompatibility, degradability, and injectivity. The outcomes of in vitro and in vivo experiments demonstrate that the hydrogel can effectively be loaded with and release curcumin liposomes, as well as silver ions, thereby facilitating diabetic wound healing through multiple mechanisms, including ROS scavenging, bactericidal activity, anti-inflammatory effects, and the promotion of angiogenesis. Transcriptome sequencing reveals that the HA@Cur@Ag hydrogel effectively suppresses the activation of the tumour necrosis factor (TNF)/nuclear factor κB (NF-κB) pathway to ameliorate oxidative stress and inflammation in diabetic wounds. These findings suggest that this ROS-responsive multifunctional injectable hydrogel, which possesses the ability to precisely coordinate and integrate intricate biological and molecular processes involved in wound healing, exhibits notable potential for expediting diabetic wound healing.
BDNF-enriched small extracellular vesicles protect against noise-induced hearing loss in mice
Authors: Xin Min, Xiao-Hui Deng, Huilin Lao, Zi-Cong Wu, Yi Chen, Yuelian Luo, Haoyang Wu, Junbo Wang, Qing-Ling Fu, Hao Xiong
Journal: Journal of Controlled Release (2023)
<i>In Vivo</i> CAR Monocytes Show Efficacy in Mice
Journal: Cancer Discovery (2023)

Abstract Preclinical data presented at the Society for Immunotherapy of Cancer Annual Meeting show the potential of cancer-targeted myeloid cells, reprogrammed in the body through the use of chimeric antigen receptor–encoding mRNA encapsulated in lipid nanoparticles, to shrink metastases and suppress tumor growth.
SIRT2 inhibition as the Achilles’ heel of ATRX-deficient gliomas
Authors: Şevin Turcan
Journal: Neuro-Oncology (2023)

Journal Article SIRT2 inhibition as the Achilles' heel of ATRX-deficient gliomas Get access Şevin Turcan Şevin Turcan Neurology Clinic and National Center for Tumor Diseases, Heidelberg University Hospital and Heidelberg University, 69120 Heidelberg, Germany (Ş.T.) Corresponding Author: Şevin Turcan, PhD, Neurology Clinic and National Center for Tumor Diseases, Heidelberg University Hospital and Heidelberg University, Heidelberg, Germany (sevin.turcan@med.uni-heidelberg.de) https://orcid.org/0000-0002-0885-5607 Search for other works by this author on: Oxford Academic PubMed Google Scholar Neuro-Oncology, Volume 26, Issue 1, January 2024, Pages 68–69, https://doi.org/10.1093/neuonc/noad217 Published: 06 November 2023 Article history Published: 06 November 2023 Corrected and typeset: 25 November 2023
Untargeted metagenomic sequencing identifies Toscana virus in patients with idiopathic meningitis, southern Spain, 2015 to 2019
Authors: Fabiana Gámbaro, Ana Belén Pérez, Matthieu Prot, Eduardo Agüera, Artem Baidaliuk, María Paz Sánchez-Seco, Luis Martínez-Martínez, Ana Vázquez, María Dolores Fernandez-Garcia, Etienne Simon-Loriere
Journal: Eurosurveillance (2023)

BackgroundVarious pathogens, including bacteria, fungi, parasites, and viruses can lead to meningitis. Among viruses causing meningitis, Toscana virus (TOSV), a phlebovirus, is transmitted through sandfly bites. TOSV infection may be suspected if patients with enterovirus- and herpesvirus-negative aseptic (non-bacterial) meningitis recall recent insect bites. Other epidemiological factors (season, rural area) may be considered. The broad range of possible meningitis aetiologies poses considerable diagnosis challenges. Untargeted metagenomic next-generation sequencing (mNGS) can potentially identify pathogens, which are not considered or detected in routine diagnostic panels.AimIn this retrospective, single-centre observational study, we investigated mNGS usefulness to understand the cause of meningitis when conventional approaches fail.MethodsCerebrospinal fluid (CSF) samples from patients hospitalised in southern Spain in 2015-2019 with aseptic meningitis and no aetiology found by conventional testing, were subjected to mNGS. Patients' demographic characteristics had been recorded and physicians had asked them about recent insect bites. Obtained viral genome sequences were phylogenetically analysed.ResultsAmong 23 idiopathic cases, TOSV was identified in eight (all male; median age: 39 years, range: 15-78 years). Five cases lived in an urban setting, three occurred in autumn and only one recalled insect bites. Phylogenetic analysis of TOSV segment sequences supported one intra-genotype reassortment event.ConclusionsOur study highlights the usefulness of mNGS for identifying viral pathogens directly in CSF. In southern Spain, TOSV should be considered regardless of recalling of insect bites or other epidemiological criteria. Detection of a disease-associated reassortant TOSV emphasises the importance of monitoring the spread and evolution of phleboviruses in Mediterranean countries.
Efficacy and Safety of Mazdutide in Chinese Patients With Type 2 Diabetes: A Randomized, Double-Blind, Placebo-Controlled Phase 2 Trial
Authors: Bo Zhang, Zhifeng Cheng, Ji Chen, Xin Zhang, Dexue Liu, Hongwei Jiang, Guoqing Ma, Xiaoyun Wang, Shenglian Gan, Juan Sun, Ping Jin, Jianjun Yi, Bimin Shi, Jianhua Ma, Shandong Ye, Guixia Wang, Linong Ji, Xuejiang Gu, Ting Yu, Pei An, Huan Deng, Haoyu Li, Li Li, Qingyang Ma, Lei Qian, Wenying Yang
Journal: Diabetes Care (2023)

OBJECTIVE We conducted a randomized, double-blind, placebo-controlled phase 2 trial to evaluate the efficacy and safety of mazdutide, a once-weekly glucagon-like peptide 1 and glucagon receptor dual agonist, in Chinese patients with type 2 diabetes. RESEARCH DESIGN AND METHODS Adults with type 2 diabetes inadequately controlled with diet and exercise alone or with stable metformin (glycated hemoglobin A1c [HbA1c] 7.0–10.5% [53–91 mmol/mol]) were randomly assigned to receive 3 mg mazdutide (n = 51), 4.5 mg mazdutide (n = 49), 6 mg mazdutide (n = 49), 1.5 mg open-label dulaglutide (n = 50), or placebo (n = 51) subcutaneously for 20 weeks. The primary outcome was change in HbA1c from baseline to week 20. RESULTS Mean changes in HbA1c from baseline to week 20 ranged from −1.41% to −1.67% with mazdutide (−1.35% with dulaglutide and 0.03% with placebo; all P &amp;lt; 0.0001 vs. placebo). Mean percent changes in body weight from baseline to week 20 were dose dependent and up to −7.1% with mazdutide (−2.7% with dulaglutide and −1.4% with placebo). At week 20, participants receiving mazdutide were more likely to achieve HbA1c targets of &amp;lt;7.0% (53 mmol/mol) and ≤6.5% (48 mmol/mol) and body weight loss from baseline of ≥5% and ≥10% compared with placebo-treated participants. The most common adverse events with mazdutide included diarrhea (36%), decreased appetite (29%), nausea (23%), vomiting (14%), and hypoglycemia (10% [8% with placebo]). CONCLUSIONS In Chinese patients with type 2 diabetes, mazdutide dosed up to 6 mg was generally safe and demonstrated clinically meaningful HbA1c and body weight reductions.
Oncolytic immunoactivation associates with survival in a glioblastoma clinical trial
Authors: Alexander L Ling, E Antonio Chiocca
Journal: Neuro-Oncology (2023)

Journal Article Oncolytic immunoactivation associates with survival in a glioblastoma clinical trial Get access Alexander L Ling, Alexander L Ling Harvey Cushing Neuro-oncology Laboratories, Department of Neurosurgery, Brigham and Women's Hospital, Boston, Massachusetts, USA Search for other works by this author on: Oxford Academic PubMed Google Scholar E Antonio Chiocca E Antonio Chiocca Harvey Cushing Neuro-oncology Laboratories, Department of Neurosurgery, Brigham and Women's Hospital, Boston, Massachusetts, USA Corresponding Author: E. Antonio Chiocca, MD, PhD, Harvey Cushing Neuro-oncology Laboratories, Department of Neurosurgery, Brigham and Women's Hospital, Boston, MA 02115, USA (eachiocca@bwh.harvard.edu) https://orcid.org/0000-0001-5183-1670 Search for other works by this author on: Oxford Academic PubMed Google Scholar Neuro-Oncology, Volume 26, Issue 2, February 2024, Pages 209–210, https://doi.org/10.1093/neuonc/noad216 Published: 06 November 2023 Article history Published: 06 November 2023 Corrected and typeset: 24 November 2023
New perspectives in cancer immunotherapy: targeting IL-6 cytokine family
Authors: Maria Florencia Soler, Andrea Abaurrea, Peio Azcoaga, Angela M Araujo, Maria M Caffarel
Journal: Journal for ImmunoTherapy of Cancer (2023)

Chronic inflammation has been recognized as a canonical cancer hallmark. It is orchestrated by cytokines, which are master regulators of the tumor microenvironment (TME) as they represent the main communication bridge between cancer cells, the tumor stroma, and the immune system. Interleukin (IL)-6 represents a keystone cytokine in the link between inflammation and cancer. Many cytokines from the IL-6 family, which includes IL-6, oncostatin M, leukemia inhibitory factor, IL-11, IL-27, IL-31, ciliary neurotrophic factor, cardiotrophin 1, and cardiotrophin-like cytokine factor 1, have been shown to elicit tumor-promoting roles by modulating the TME, making them attractive therapeutic targets for cancer treatment. The development of immune checkpoint blockade (ICB) immunotherapies has radically changed the outcome of some cancers including melanoma, lung, and renal, although not without hurdles. However, ICB shows limited efficacy in other solid tumors. Recent reports support that chronic inflammation and IL-6 cytokine signaling are involved in resistance to immunotherapy. This review summarizes the available preclinical and clinical data regarding the implication of IL-6-related cytokines in regulating the immune TME and the response to ICB. Moreover, the potential clinical benefit of combining ICB with therapies targeting IL-6 cytokine members for cancer treatment is discussed.
Dominant CD4+ T cell receptors remain stable throughout antiretroviral therapy-mediated immune restoration in people with HIV
Authors: Alexis Sponaugle, Ann Marie K. Weideman, Jolene Ranek, Gatphan Atassi, JoAnn Kuruc, Adaora A. Adimora, Nancie M. Archin, Cynthia Gay, Daniel R. Kuritzkes, David M. Margolis, Benjamin G. Vincent, Natalie Stanley, Michael G. Hudgens, Joseph J. Eron, Nilu Goonetilleke
Journal: Cell Reports Medicine (2023)

In people with HIV (PWH), the post-antiretroviral therapy (ART) window is critical for immune restoration and HIV reservoir stabilization. We employ deep immune profiling and T cell receptor (TCR) sequencing and examine proliferation to assess how ART impacts T cell homeostasis. In PWH on long-term ART, lymphocyte frequencies and phenotypes are mostly stable. By contrast, broad phenotypic changes in natural killer (NK) cells, γδ T cells, B cells, and CD4+ and CD8+ T cells are observed in the post-ART window. Whereas CD8+ T cells mostly restore, memory CD4+ T subsets and cytolytic NK cells show incomplete restoration 1.4 years post ART. Surprisingly, the hierarchies and frequencies of dominant CD4 TCR clonotypes (0.1%–11% of all CD4+ T cells) remain stable post ART, suggesting that clonal homeostasis can be independent of homeostatic processes regulating CD4+ T cell absolute number, phenotypes, and function. The slow restoration of host immunity post ART also has implications for the design of ART interruption studies.
‘More than likely the men come first. That’s just very frustrating’. A qualitative exploration of contextual factors affecting the implementation of injury prevention initiatives and the provision of effective injury management in elite-level women’s club football in Ireland
Authors: Dan Horan, Eamonn Delahunt, Mark Roe, Martin Hägglund, Catherine Blake, Seamus Kelly
Journal: British Journal of Sports Medicine (2023)

Objectives The aim of our study was to explore the contextual factors that affect the implementation of football injury prevention initiatives and the provision of effective injury management in the Irish Women’s National League (WNL). Methods We used a criterion-based purposive sampling approach to recruit coaches (n=7), players (n=17) and medical personnel (n=8) representing eight of the nine clubs in the WNL to participate in one-to-one semistructured interviews. Our study was located within an interpretivist, constructivist research paradigm. The interview data were analysed using reflexive thematic analysis. Results The participants identified academic and work pressures, financial challenges, conflict with college football, inadequate facilities and gender inequity as being barriers to the implementation of injury prevention initiatives and the provision of effective injury management. Financial constraints within clubs were perceived to limit the provision of medical care and strength and conditioning (S&amp;C) support and this was deemed to be associated with a heightened risk of injuries. Conclusion Specific contextual factors were identified which curtail the implementation of injury prevention initiatives and the provision of effective injury management in elite-level women’s club football in Ireland. Gender inequity was identified as one of the factors impacting the availability of high-quality medical care, S&amp;C support, as well as access to training and match facilities. Our results provide new insights that could be used to inform the design and implementation of injury prevention and management initiatives for women football players in Ireland.
Biallelic Cys141Tyr variant of SEL1L is associated with neurodevelopmental disorders, agammaglobulinemia, and premature death
Authors: Denisa Weis, Liangguang L Lin, Huilun H Wang, Zexin Jason Li, Katarina Kusikova, Peter Ciznar, Hermann M Wolf, Alexander Leiss-Piller, Zhihong Wang, Xiaoqiong Wei, Serge Weis, Katarina Skalicka, Gabriela Hrckova, Lubos Danisovic, Andrea Soltysova, Tingxuan T Yang, René Günther Feichtinger, Johannes A Mayr, Ling Qi
Journal: Journal of Clinical Investigation (2023)

Suppressor of lin-12-like-HMG-CoA reductase degradation 1 (SEL1L-HRD1) ER-associated degradation (ERAD) plays a critical role in many physiological processes in mice, including immunity, water homeostasis, and energy metabolism; however, its relevance and importance in humans remain unclear, as no disease variant has been identified. Here, we report a biallelic SEL1L variant (p. Cys141Tyr) in 5 patients from a consanguineous Slovakian family. These patients presented with not only ERAD-associated neurodevelopmental disorders with onset in infancy (ENDI) syndromes, but infantile-onset agammaglobulinemia with no mature B cells, resulting in frequent infections and early death. This variant disrupted the formation of a disulfide bond in the luminal fibronectin II domain of SEL1L, largely abolishing the function of the SEL1L-HRD1 ERAD complex in part via proteasomal-mediated self destruction by HRD1. This study reports a disease entity termed ENDI-agammaglobulinemia (ENDI-A) syndrome and establishes an inverse correlation between SEL1L-HRD1 ERAD functionality and disease severity in humans.
Tom Nolan’s research reviews—9 November 2023
Authors: Tom Nolan
Journal: BMJ (2023)

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